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随便翻译了一下,很古老的帖子,前两天在论坛看到有帖子介绍,就跑去看了看,搜了搜发现没人翻译,就自己随便翻译了一下(英语和医药知识都很薄弱),就当给自己科普了D2OL的研究过程.
原文在 http://www.d2ol.com/cgi-bin/ulti ... _topic;f=1;t=000149
这里有过转载 http://www.equn.com/forum/viewth ... amp;page=1#pid53768
想把自己的翻译发上来,但又不知道该发在哪里,也不知道有没有人会看,不过纯当兴趣,抱着与大家分享(以及接受大家指正)的态度,呵呵~
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原文
How D2OL will help cure SARS
posted May 15, 2003 05:18 PM
To all members of the D2OL community,
My name is Dr. Bonnie Gould Rothberg and I am the Medical Director of the Rothberg Institute, your D2OL host. On behalf of The Rothberg Institute, I would like to thank you for your time and efforts in helping us crunch towards a cure for SARS.
The strengths of a global community working in harmony have really been a driving force behind all areas of SARS research. The SARS epidemic was first brought to international attention in February and scientists from all over the world have been working at breakneck speeds towards getting at the heart of SARS. In fact, in less than 3 months, this international collaboration has led to the identification of the virus that causes SARS, the complete identification of its genetic code (i.e., its DNA sequence) and, most recently, identification of a key protein made by the SARS virus that, if shut down by a drug, could stop the SARS infection. The speed of this progress probably sets a new world record for scientific discovery. For those who wish to read the scientific literature on SARS, please visit www.nejm.org for the May 15th issue of the New England Journal Of Medicine and www.sciencemag.org for the genetic code of the SARS virus and the protein structure of this key target.
Amid this backdrop of breakneck discovery, you all have volunteered computer time to our D2OL effort against SARS. I would, then like to update you all of the progress on this project and inform you of the scientific strategy behind the SARS arm of D2OL.
1. Selection of a target for SARS
Since we posted our SARS target close to 4 weeks ago, folks have wanted to learn more about the target we selected and how interfering with this particular target will ultimately stop the SARS infection. A simple explanation follows.
The SARS virus is a member of the coronavirus, or crown-virus (under the microscope, they look like they wear crowns), family. And, to a large extent, all coronaviruses are related. So, while scientists are still learning about the intricacies of the SARS virus, there are 7 other coronaviruses that scientists are much more familiar with and have been, in fact, studying for over 30 years. Over the years, scientists have come to learn about many aspects of the coronavirus life cycle-facts that are common to all members of the coronavirus family. So, when we learned 4 weeks ago that the SARS virus was a coronavirus, even without having lots of knowledge about the specifics about the SARS virus we could apply basic ideas common to all coronaviruses to SARS. And that is what we did.
All coronaviruses make a protein called the "Coronavirus Main Protease" or 3CL-PRO , for short. This protein is absolutely essential for the virus to make copies of itself and spread the infection, so stopping this protein from working would very likely stop the virus. This protein is also very sexy from a drug development standpoint. Pharmaceutical companies already know how to make drugs that inhibit proteases made by viruses (e.g., ritonavir and indinavir are major components of anti-HIV drug regimens). It also turns out that the Agouron division of Pfizer has already successfully made drugs against the 3CL-PRO protein found in the virus responsible for the common cold (rhinovirus). The Coronavirus Main Proteinase is, therefore, an excellent drug target for anti-SARS therapy and why we selected this target 4 weeks ago.
2. Of Pigs and Man
As many of the techies already know, to prepare a drug target to work in a docking environment, it is essential that its X-ray crystal structure be solved. This work is typically done by expert biophysicists working in either industrial or academic labs. In order for D2OL to consider drug discovery against 3CL-PRO, we needed the coordinates for the protein as determined by X-ray crystal structure. Four weeks ago, (before the SARS virus was characterized) we were very fortunate to find that a group working in Germany had, a few years back, worked out the X-ray crystal structure for the 3CL-PRO from a coronavirus that causes diarrhea in pigs ( the transmissible gastroenteritis virus, TGEV ). Because we knew that all coronaviruses are very similar to each other, we made the basic assumption that since the 3CL-PRO was so essential for the coronavirus to work properly that the 3CL-PRO structure was likely to be very similar if not identical among all members of the coronavirus family. We had some evidence of this from the German group who, in their work from 2001, had shown that the key pieces of the 3CL-PRO protein were identical across all 7 of the coronaviruses they looked at. We thus uploaded to the community the 3CL-PRO identified from the pig coronavirus TGEV as a target that will help us find drugs against SARS. Just yesterday, the same German group that previously worked on the TGEV structure published in the journal Science (if you publish here, you are a star and you are made [Cool] ) that they solved the structure for 3CL-PRO from a coronavirus that causes a variety of the human cold (a.k.a. HCo-V) and based on this structure and that from the TGEV, they were able to deduce the structure of the SARS coronavirus 3CL-PRO. Their conclusions were as follows:
1. As per our assumption, the guts of the 3CL-PRO (the parts that make it work correctly) are the similar enough across all coronaviruses such that drugs that are useful for one type should be useful for all
2. Based on the work done by the Agouron scientists, the German team concluded that 3CL-PRO would be an outstanding target to stop SARS.
But we all already knew this 4 weeks ago [Big Grin] .
3. So what's next? .
First and foremost, at The Rothberg Institute, we are scientists. Now that we have spent our 5 minutes patting ourselves on the back for picking the right target in 3CL-PRO, we have been very carefully reading the Science paper from the German group and using it to help us put together an action plan. I would like to share that plan with you all.
A. Updating and adding more SARS targets. Now that the actual X-ray crystal structure for the 3CL-PRO from the HCo-V human coronavirus is known and the SARS version is strongly suggested, we will be adding these ASAP (should be up by the end of the month) as SARS targets II & III. By crunching all 3 flavors of the coronavirus 3CL-PRO, we should be able to identify candidate molecules that are ranked as top candidates for all 3 targets. We hope that the probability of getting a drug to score high for all 3 targets by chance alone is much less than if it is due to real chemical factors. Candidates making the tops of all 3 lists then have a better chance of owrking at the lab bench, thus speeding up our efforts.
B. Learning from Agouron/Pfizer. As I have mentioned, the scientists at Agouron have already worked extensively with the cold virus (rhinovirus) 3CL-PRO and have even made drugs that have tight binding to it. All of this has been published in the scientific literature. We would like to leverage their knowledge to help make our effort more tightly controlled. Firstly, we will also load up a 4th target, the 3CL-PRO from the rhinovirus-the same one that Agouron worked on. So don't be surprised when folks see this target as one to crunch. We are also going to load up all of the chemicals that Agouron has published that bind to the the rhinovirus 3CL-PRO and mix these up with the candidates that we already have. Then we will see if our computer can pull up the Agouron molecules as strong candidates for the rhinovirus 3CL-PRO (it should). If it does, we know for certain that our program is optimized to crunch for good targets for 3CL-PROs. If we get less than perfect results, our computational chemists on staff will be put to the task of tweaking D2OL to get a better fit between the Agouron drugs and the rhinovirus 3CL-PRO. For the non-scientists out there, this part of the experiment is called the "control" and is an essential part for any experiment. Good controls are what sets apart good science from hocus-pocus magic.
Please do look for the new changes to your D2OL client in the next few weeks. And, as always, we'll be posting updates when these changes are about to happen.
We will also be happy to respond to members of the community who may have additional questions.
Thanks,
Dr. Bonnie |
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